The hypothesis for this proposal is that plasma factors, including tumor necrosis factor (TNF)- alpha and anti-CD36 antibodies, play a major etiologic role in TTP associated with HIV infection through induction of endothelial cell (EC) apoptosis. This is based upon four preliminary observations: the ability of these sera to induce apoptosis in microvascular but not large vessel EC; the upregulation of TNF-alpha in a small subset of HIV+ patients to concentrations associated with programmed cell death of EC in vitro; the relationship of CD36 cross-linking to activation of protein phosphokinases implicated in induction of apoptosis; and the expression of one membrane molecule critical to apoptosis, Fas, on subsets of microvascular EC, and its upregulation by TTP sera. We will examine the immunobiology of human microvascular EC in terms of interactions with TTP sera and plasma from HIV+ and HIV seronegative individuals, TNF-alpha, anti-CD36 isolated from patients with TTP, and HIV-infected monocytes. Specificity will be sought in parallel experiments with large vessel EC, which are not affected by the pathologic process of TTP. This proposal attempts to unify and interrelate several distinct observations characteristic of TTP: development of platelet thromboses limited to the microvasculature, accompanied by EC proliferation, damage, and exposure of subendothelial layers, all in the absence of an inflammatory response. Based upon the likelihood that both Fas/Fas ligand interactions and CD36 cross- linking are facilitated by TTP plasma factors, leading to microvascular EC activation, protein kinase induction, and EC apoptosis as well as platelet aggregation, we will examine the possibility of developing specific treatments for TTP based upon protein kinase inhibitors and CD36 peptides. (End of Abstract)